This research project uses novel technology and innovative strategies to discover molecular differences between foveal cones and extrafoveal cells and to identify alterations in photoreceptor cell gene expression in early AMD. A comprehensive interrogation of gene expression in foveal and extrafoveal cones will be important to the field for at least 4 reasons: (1) foveal cones are the most important cells for visual acuity, and hence are critical targets for gene augmentation therapy and a better understanding of their physiology will be important for the development of stem cell directed therapies; (2) foveal cones persist for years in some patients with AMD, leaving a ring scotoma but good acuity, and understanding why they survive may lead to approaches to help rescue other photoreceptor cells from degeneration; (3) rod photoreceptors are likely to yield insight into the delayed dark adaptometry phenotype in AMD; (4) a biological understanding for the morphological differences in foveal and extrafoveal cones is currently lacking. All of these important biological and translational questions will be addressed by the proposed study. The ultimate goal of this research proposal is to identify a set of molecules that can: (1) improve gene augmentation and stem cell directed therapies; (2) determine why foveal cones are alternatively spared or targeted by different retinal diseases; and (3) determine the mechanism underlying the delayed dark adaptation phenotype in AMD patients. These latter outcomes will improve the accuracy of the clinical prognosis for AMD patients, and will lead to new avenues of investigation to delay vision loss, and extend the lifetime of visual acuity in patients with AMD.